The 78-kDa
glucose-regulated
protein (
GRP78) is a well-established endoplasmic reticulum (ER)-resident chaperone that maintains protein homeostasis and regulates the unfolded protein response. Under conditions of ER stress,
GRP78 is also expressed at the cell surface and implicated in
tumorigenesis, immunity, and cellular signaling events. The role of cell surface-associated
GRP78 (csGRP78) in the pathogenesis of
diabetic nephropathy has not yet been defined. Here we explored the role of csGRP78 in regulating high
glucose (HG)-induced profibrotic AKT Ser/Thr
kinase (AKT) signaling and up-regulation of
extracellular matrix proteins. Using primary kidney mesangial cells, we show that HG treatment, but not the osmotic control
mannitol, induces csGRP78 expression through an ER stress-dependent mechanism. We found that csGRP78, known to be located on the outer membrane leaflet, interacts with the transmembrane
protein integrin β1 and activates
focal adhesion kinase and downstream PI3K/AKT signaling. Localization of
GRP78 at the cell surface and its interaction with
integrin β1 were also required for
extracellular matrix protein synthesis in response to HG. Surprisingly, both the N and C termini of csGRP78 were necessary for this profibrotic response. Increased localization of
GRP78 at the plasma membrane was also found in the glomerular mesangial area of type 1 diabetic mice in two different models (
streptozotocin-induced and Akita). In freshly isolated glomeruli from Akita mice, csGRP78 co-localized with the mesangial cell surface marker α8-integrin. In conclusion, our work reveals a role for csGRP78 in HG-induced profibrotic responses in mesangial cells, informing a potential approach to treating
diabetic nephropathy.